There is a well-established link between influenza virus infection and secondary infections with bacteria, such as Haemophilus influenzas. These secondary bacterial infections cause pneumonia or meningitis and result in considerable morbidity and mortality, particularly in young children, debilitated elderly and immunocompromised individuals. Secondary bacterial infections may also significantly increase mortality in the human population as whole during influenza pandemics. Thus highly virulent strains of influenza whether naturally-occurring or engineered, could even predispose normal immunocompetent individuals to severe illness upon secondary bacterial infection. However, in spite of the significance of this problem for human health, the interactions between these agents that lead to more severe illness are poorly understood. We have established a mouse model in which we have observed lethal synergy between influenza and H. influenzae when the two agents are administered sequentially. In the current application, we will further develop this small animal model to dissect the mechanisms underlying severe illness or lethality induced by the interaction of influenza and H. Influenzae. Our hypothesis is that sequential administration of influenza and H. Influenzae subverts the immune response resulting in lethal tissue damage in the lung. We suggest that aberrant cytokine and chemokine production plays a major role in this process and will focus on this aspect of the response in this two-year application. We will determine i) how the cytokine/chemokine profile differs during infection with both agents as oppose to either agent alone, ii) whether increased bacterial or viral loads play a role in altered cytokine production iii) the cell types contributing to inflammation and the type of damage induced in the lung and iv) the role of selected cytokines in lethal synergy between H. influenzae and influenza. The data obtained in these studies will further our understanding of how the two infectious agents interact and will provide a firm basis for additional studies. This is consistent with the exploratory/developmental nature of the R21 application. Such studies may ultimately lead to the development of specific interventions to prevent excessive lung damage in individuals co-infected with viruses and bacteria. This could be particularly important during an influenza pandemic and may be more broadly applicable to other respiratory viruses. [unreadable] [unreadable] [unreadable]